tbuckley/cabot-search huggingface dataset:
Long-term oral antibiotic use in people with acne vulgaris in UK primary care: a drug utilization study
Authors: Ketaki Bhate, Kathryn E Mansfield, Sarah-Jo Sinnott, David J Margolis, Elizabeth  Adesanya, Nick Francis, Clemence Leyrat, Susan Hopkins, Richard Stabler, Laura Shallcross, Sinéad M Langan, Rohini Mathur
Journal: British Journal of Dermatology (2022)

Abstract Background The inappropriate use of antibiotics is understood to contribute to antimicrobial resistance. Oral antibiotics are regularly used to treat moderate-to-severe acne vulgaris. In practice, we do not know the typical length of oral antibiotic treatment courses for acne in routine primary care and what proportion of people receive more than one course of treatment following a new acne diagnosis. Objectives To describe how oral antibiotics are prescribed for acne over time in UK primary care. Methods We conducted a descriptive longitudinal drug utilization study using routinely collected primary care data from the Clinical Practice Research Datalink GOLD (2004–2019). We included individuals (8–50 years) with a new acne diagnosis recorded between 1 January 2004 and 31 July 2019. Results We identified 217 410 people with a new acne diagnosis. The median age was 17 years [interquartile range (IQR) 15–25] and median follow-up was 4.3 years (IQR 1.9–7.6). Among people with a new acne diagnosis, 96 703 (44.5%) received 248 560 prescriptions for long-term oral antibiotics during a median follow-up of 5.3 years (IQR 2.8–8.5). The median number of continuous courses of antibiotic therapy (≥ 28 days) per person was four (IQR 2–6). The majority (n = 59 010, 61.0%) of first oral antibiotic prescriptions in those with a recorded acne diagnosis were between the ages of 12 and 18. Most (n = 71 544, 74.0%) first courses for oral antibiotics were for between 28 and 90 days. The median duration of the first course of treatment was 56 days (IQR 50–93 days) and 18 127 (18.7%) of prescriptions of ≥ 28 days were for &amp;lt; 6 weeks. Among people who received a first course of oral antibiotic for ≥ 28 days, 56 261 (58.2%) received a second course after a treatment gap of ≥ 28 days. The median time between first and second courses was 135 days (IQR 67–302). The cumulative duration of exposure to oral antibiotics during follow-up was 255 days (8.5 months). Conclusions Further work is needed to understand the consequences of using antibiotics for shorter periods than recommended. Suboptimal treatment duration may result in reduced clinical effectiveness or repeated exposures, potentially contributing to antimicrobial resistance.
Cross-specialty identification of the JAK1 inhibitor trial agent filgotinib as a potential therapy for alopecia areata
Authors: Nicole Fagan, Glen A Doherty, Nekma  Meah, Rodney Sinclair, Dmitri  Wall
Journal: British Journal of Dermatology (2022)

First report of alopecia areata responding to the selective JAK1 inhibitor filgotinib. This case is a patient with coinciding Crohn’s disease that had failed multiple biologics. It serves as a real-world example of how shared decision making between physicians can greatly improve patient outcomes. It highlights that sharing patient registry datasets between specialties will have great benefits, for example in repurposing of JAK inhibitors for other conditions.
Base editing screens map mutations affecting interferon-γ signaling in cancer
Authors: Matthew A Coelho, Sarah Cooper, Magdalena E Strauss, Emre Karakoc, Shriram Bhosle, Emanuel Gonçalves, Gabriele Picco, Thomas Burgold, Chiara M Cattaneo, Vivien Veninga, Sarah Consonni, Cansu Dinçer, Sara F Vieira, Freddy Gibson, Syd Barthorpe, Claire Hardy, Joel Rein, Mark Thomas, John Marioni, Emile E Voest, Andrew Bassett, Mathew J Garnett
Journal: Cancer Cell (2023)

Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.
Humoral signatures of MOG-antibody-associated disease track with age and disease activity
Authors: Marianna Spatola, Omar Chuquisana, Wonyeong Jung, Joseph A Lopez, Eva-Maria Wendel, Sudarshini Ramanathan, Christian W Keller, Tim Hahn, Edgar Meinl, Markus Reindl, Russell C Dale, Heinz Wiendl, Douglas A Lauffenburger, Kevin Rostásy, Fabienne Brilot, Galit Alter, Jan D Lünemann
Journal: Cell Reports Medicine (2023)

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.
Re: Yaw A. Nyame, Matthew R. Cooperberg, Marcus G. Cumberbatch, et al. Deconstructing, Addressing, and Eliminating Racial and Ethnic Inequities in Prostate Cancer Care. Eur Urol 2022;82:341–51
Authors: Maria Maddalena Sirufo, Lia Ginaldi, Massimo De Martinis
Journal: European Urology (2023)
stAPAminer: Mining Spatial Patterns of Alternative Polyadenylation for Spatially Resolved Transcriptomic Studies
Authors: Guoli Ji, Qi Tang, Sheng Zhu, Junyi Zhu, Pengchao Ye, Shuting Xia, Xiaohui Wu
Journal: Genomics Proteomics & Bioinformatics (2023)

Abstract Alternative polyadenylation (APA) contributes to transcriptome complexity and gene expression regulation and has been implicated in various cellular processes and diseases. Single-cell RNA sequencing (scRNA-seq) has enabled the profiling of APA at the single-cell level; however, the spatial information of cells is not preserved in scRNA-seq. Alternatively, spatial transcriptomics (ST) technologies provide opportunities to decipher the spatial context of the transcriptomic landscape. Pioneering studies have revealed potential spatially variable genes and/or splice isoforms; however, the pattern of APA usage in spatial contexts remains unappreciated. In this study, we developed a toolkit called stAPAminer for mining spatial patterns of APA from spatially barcoded ST data. APA sites were identified and quantified from the ST data. In particular, an imputation model based on the k-nearest neighbors algorithm was designed to recover APA signals, and then APA genes with spatial patterns of APA usage variation were identified. By analyzing well-established ST data of the mouse olfactory bulb (MOB), we presented a detailed view of spatial APA usage across morphological layers of the MOB. We compiled a comprehensive list of genes with spatial APA dynamics and obtained several major spatial expression patterns that represent spatial APA dynamics in different morphological layers. By extending this analysis to two additional replicates of the MOB ST data, we observed that the spatial APA patterns of several genes were reproducible among replicates. stAPAminer employs the power of ST to explore the transcriptional atlas of spatial APA patterns with spatial resolution. This toolkit is available at https://github.com/BMILAB/stAPAminer and https://ngdc.cncb.ac.cn/biocode/tools/BT007320.
Acceptance, safety and immunogenicity of a booster dose of inactivated SARS-CoV-2 vaccine in adults with tuberculosis
Authors: Haoting Zhan, Li Yang, Yongmei Liu, Haolong Li, Xiaomeng Li, Haibin Wang, Jinfeng Cao, Shuhui Kang, Xinru Guo, Erhei Dai, Yongzhe Li
Journal: Journal of Infection (2023)
Photomodulated Extrusion as a Localized Endovascular Hydrogel Deposition Method
Authors: Yuta Dobashi, Jerry C. Ku, Joel Ramjist, Christopher Pasarikovski, Konrad Walus, John D. W. Madden, Victor X. D. Yang
Journal: Advanced Healthcare Materials (2023)

Minimally invasive endovascular embolization is used to treat a wide range of diseases in neurology, oncology, and trauma where the vascular morphologies and corresponding hemodynamics vary greatly. Current techniques based on metallic coils, flow diverters, liquid embolics, and suspended microspheres are limited in their ability to address a wide variety of vasculature and can be plagued by complications including distal migration, compaction, and inappropriate vascular remodeling. Further, these endovascular devices currently offer limited therapeutic functions beyond flow control such as drug delivery. Herein, a novel in situ microcatheter-based photomodulated extrusion approach capable of dynamically tuning the physical and morphological properties of injectable hydrogels, optimizing for local hemodynamic environment and vascular morphology, is proposed and demonstrated. A shear thinning and photoactivated poly(ethylene glycol diacrylate)-nanosilicate (PEGDA-nSi) hydrogel is used to demonstrate multiple extrusion modes which are controlled by photokinetics and device configurations. Real-time photomodulation of injected hydrogel viscosity and modulus is successfully used for embolization in various vasculatures, including high-flow large vessels and arterial-to-arterial capillary shunts. Furthermore, a generalizable therapeutic delivery platform is proposed by demonstrating a core-shell structured extrusion encapsulating doxorubicin to achieve a more sustained release compared to unencapsulated payload.
Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency
Authors: Laura Guantay, Cintia Garro, Sebastián Siri, María Florencia Pansa, Sonja Ghidelli-Disse, Natalia Paviolo, Ana Racca, Viviana Nicotra, Caius Radu, José Luis Bocco, Rosana Felice, Keith H. Jansson, Katja Remlinger, Alejandro Amador, Euan Stronach, Kevin Coleman, Marcel Muelbaier, Gerard Drewes, Isro Gloger, Kevin Madauss, Manuela García, Vanesa Gottifredi, Gastón Soria
Journal: Drug Resistance Updates (2023)
Co-delivery of gemcitabine and paclitaxel plus NanoCpG empowers chemoimmunotherapy of postoperative “cold” triple-negative breast cancer
Authors: Beibei Guo, Yan Qu, Yinping Sun, Songsong Zhao, Jiandong Yuan, Peizhuo Zhang, Zhiyuan Zhong, Fenghua Meng
Journal: Bioactive Materials (2023)

Triple-negative breast cancer (TNBC) due to lack of clear target and notorious "cold" tumor microenvironment (TME) is one of the most intractable and lethal malignancies. Tuning "cold" TME into "hot" becomes an emerging therapeutic strategy to TNBC. Herewith, we report that integrin-targeting micellar gemcitabine and paclitaxel (ATN-mG/P, ATN sequence: Ac-PhScNK-NH2) cooperating with polymersomal CpG (NanoCpG) effectively "heated up" and treated TNBC. ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells, induced potent immunogenic cell death (ICD), and efficiently stimulated maturation of bone marrow-derived dendritic cells (BMDCs). Remarkably, in a postoperative TNBC model, ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses, showing a greatly augmented proportion of mature DCs and CD8+ T cells while reduced immune-suppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg), which led to complete inhibition of lung metastasis and 60% mice tumor-free. The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of "cold" tumors like TNBC.
Total Hip Replacement
Authors: David G. Murray
Journal: JAMA (1995)

<h3>Objective.</h3> —To provide physicians with a current consensus on total hip replacement. <h3>Participants.</h3> —A nonfederal, nonadvocate, 13-member consensus panel representing the fields of orthopedic surgery, rehabilitation and physical medicine, biomechanics and biomaterials, internal medicine, public health, geriatrics, biostatistics, and a public representative. In addition, 27 experts in orthopedic surgery, rehabilitation and physical medicine, biomechanics and biomaterials, rheumatology, geriatrics, and epidemiology presented data to the consensus panel and a conference audience of 425. <h3>Evidence.</h3> —The literature was searched through MEDLINE and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. <h3>Consensus.</h3> —The panel, answering predefined consensus questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. <h3>Consensus Statement.</h3> —The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. <h3>Conclusions.</h3> —Total hip replacement is an option for nearly all patients with diseases of the hip that cause chronic discomfort and significant functional impairment. Most patients have an excellent prognosis for long-term improvement in symptoms and physical function. At this time, a cemented femoral component using modern cementing techniques, paired with a porous-coated acetabular component, can give excellent long-term results. Revision of a total hip replacement is indicated when mechanical failure occurs. Continued periodic follow-up is necessary to identify early evidence of impending failure so as to permit remedial action before a catastrophic event. (<i>JAMA</i>. 1995;273:1950-1956)
Dietary Fat Predicts Conversion From Impaired Glucose Tolerance to NIDDM: The San Luis Valley Diabetes Study
Authors: Julie A Marshall, Sharon Hoag, Susan Shetterly, Richard F Hamman
Journal: Diabetes Care (1994)

OBJECTIVE To determine if dietary fat intake measured at a baseline exam in subjects with impaired glucose tolerance (IGT) predicted the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Based on an oral glucose tolerance test (OGTT) (World Health Organization criteria), we identified 134 eligible subjects with IGT from a geographically based sample of subjects with no prior history of diabetes. One to three years after the baseline exam, 123 subjects (92%) had a repeat OGTT. Diet was assessed by a 24-h diet recall reported before the baseline OGTT. RESULTS The mean percentage of energy eaten as fat was 43.4% in 20 people subsequently developing NIDDM compared with 40.6% in 43 people remaining IGT and 38.9% in 60 subjects who subsequently reverted to normal glucose tolerance. In comparing the 20 subjects who developed NIDDM with the 103 who remained IGT or normal, an increase in fat intake of 40 g/day was associated with an increase in risk of NIDDM of 3.4-fold (95% confidence interval [CI] 0.8–13.6) adjusted for energy intake, age, sex, ethnicity, and obesity. The odds ratio increased to sixfold (95% CI 1.2–29.8) after adjustment for fasting glucose, insulin, and 1-h insulin. CONCLUSIONS Fat consumption significantly predicts NIDDM risk in subjects with IGT after controlling for obesity and markers of glucose metabolism.
Suicidal ideation in patients with rheumatoid arthritis
Authors: G. J Treharne
Journal: BMJ (2000)

Sentinel node biopsy for malignant melanoma Having this biopsy gives psychological benefitsEditor-The editorial by Thomas and Patocskai summarises the current state of sentinel lymph node biopsy for malignant melanoma. 1 What the authors omitted to address was patients' perception of the procedure.Anecdotal evidence suggests that patients with melanoma derive psychological benefit from having the procedure, regardless of the result.To investigate any such benefit our unit carried out a study looking at the acceptability and benefits of the procedure.A specially designed questionnaire was sent to 110 patients who had undergone the procedure between August 1997 and February 1999.Ninety eight patients (89%) replied, including all those in whom the result had been positive (19/110).To study any time dependent trends the respondents were subdivided into three subgroups, depending on length of follow up (table).Most patients (95/98) were glad that they had had the procedure, though the effects decreased with time (table).Overall 89 of the patients believed that they had gained some benefit from the biopsy, and 96 said that they would recommend it to other patients.Most patients with melanoma undoubtedly derive at least short term psychological benefits from having a sentinel lymph node biopsy.This effect seems to be independent of the result of the biopsy itself.The decreased reassurance with time may simply represent a time dependent factor but might be due to the frequent clinic visits and additional biopsies of suspicious lesions, which cause increased anxiety in patients with melanoma. 2 The procedure has high patient acceptability and offers patients a proactive option in addition to regular clinic reviews after initial diagnosis.It does not, however, seem greatly to influence patients' worries about being "cured" or fully enable patients to plan for the future.The small psychological benefit shown in our study cannot be used to justify routine sentinel lymph node biopsy in patients with melanoma.The cost and morbidity of this procedure must be balanced by proved survival benefit.We agree with others that until such benefit is shown, sentinel lymph node biopsy should be offered only in a multidisciplinary setting as part of a clinical trial. 1 3
Corticosteroid-binding globulin (CBG): spatiotemporal distribution of cortisol in sepsis
Authors: Jessica H. Lee, Emily J. Meyer, Marne A. Nenke, Henrik Falhammar, David J. Torpy
Journal: Trends in Endocrinology and Metabolism (2023)

Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.
Amyloid Fibrils Enhance the Topical Bio‐Adhesivity of Liquid Crystalline Mesophase‐Based Drug Formulations
Authors: Francesca Damiani Victorelli, Camila Fernanda Rodero, Viviane Lutz‐Bueno, Marlus Chorilli, Raffaele Mezzenga
Journal: Advanced Healthcare Materials (2023)

Despite their distinctive secondary structure based on cross β-strands, amyloid fibrils (AF) are stable fibrous protein aggregates with features similar to collagen, one of the main components of the extracellular matrix, and thus constitute a potential scaffold for enhancing cell adhesion for topical applications. Here, the contribution of AF to skin bio-adhesivity aiming toward topical treatments is investigated. Liquid crystalline mesophase (LCM) based on phytantriol is formulated, with the aqueous phase containing either water or a solution of 4 wt% amyloid fibrils. Then resveratrol is added as a model anti-inflammatory molecule. The developed LCM presents a double gyroid Ia3d mesophase. The incorporation of AF into the LCM increases its bio-adhesive properties. In vitro release and ex vivo permeation and retention confirm the controlled release property of the system, and that resveratrol is retained in epidermis and dermis, but is also permeated through the skin. All formulations are biocompatible with L929 cells. The in vivo assay confirms that systems with AF lead to a higher anti-inflammatory effect of resveratrol. These results confirm the hypothesis that the incorporation of AF in the LCM increases the bio-adhesiveness and efficiency of the system for topical treatment, and consequently, the therapeutical action of the encapsulated drug.
T cell exhaustion in malignant gliomas
Authors: Matthew B. Watowich, Mark R. Gilbert, Mioara Larion
Journal: Trends in cancer (2023)

Despite advances in understanding tumor biology, malignant gliomas remain incurable. While immunotherapy has improved outcomes in other cancer types, comparable efficacy has not yet been demonstrated for primary cancers of the central nervous system (CNS). T cell exhaustion, defined as a progressive decrease in effector function, sustained expression of inhibitory receptors, metabolic dysfunction, and distinct epigenetic and transcriptional alterations, contributes to the failure of immunotherapy in the CNS. Herein, we describe recent advances in understanding the drivers of T cell exhaustion in the glioma microenvironment. We discuss the extrinsic and intrinsic factors that contribute to exhaustion and highlight potential avenues for reversing this phenotype. Our ability to directly target specific immunosuppressive drivers in brain cancers would be a major advance in immunotherapy.
Corrigendum to “Novel retinal vascular phenotypes for the potential assessment of long-term risk in living kidney donors.” Kidney Int. 2022;102:661–665
Authors: Ylenia Giarratano, Dan Pugh, Tariq E. Farrah, Gabriel C. Oniscu, Thomas J. MacGillivray, Baljean Dhillon, Neeraj Dhaun, Miguel O. Bernabeu
Journal: Kidney International (2023)

DOI of original article: https://doi.org/10.1016/j.kint.2022.06.019 The authors regret that Supplementary Tables S1–S3 and Supplementary Figures S1 and S2 were inadvertently not included with the published Supplementary Material. The authors would like to apologize for any inconvenience caused. Download .pdf (1.67 MB) Help with pdf files Supplementary File (PDF) Novel retinal vascular phenotypes for the potential assessment of long-term risk in living kidney donorsKidney InternationalVol. 102Issue 3PreviewChronic kidney disease (CKD) has a global prevalence of ≈10% and is independently associated with incident cardiovascular disease (CVD).1 The risk of CVD increases as estimated glomerular filtration rate (eGFR) declines and is highest in those with kidney failure.1 Kidney transplantation prolongs survival of patients with kidney failure, and transplantation of a kidney from a living donor is considered the optimal form of renal replacement therapy. However, kidney donation may be associated with longer-term risks of developing both CKD and CVD. Full-Text PDF Open Access